Afatinib in EGFR TKI-naïve patients with EGFR-mutation positive NSCLC:

interim analysis from a Phase IIIb, open-label study

Filippo de Marinis,1 Konstantin K Laktionov,2 Artem Poltoratskiy,3 Inna Egorova,4

Maximilian Hochmair,5 Antonio Passaro,1 Maria Rita Migliorino,6 Giulio Metro,7 Maya Gottfried,8 Daphne Tsoi,9 Gyula Ostoros,10 Simona Rizzato,11 Guzel Z Mukhametshina,12

Michael Schumacher,13 Silvia Novello,14 Rafal Dziadziuszko,15 Wenbo Tang,16

Laura Clementi,17 Agnieszka Cseh,18 Dariusz Kowalski19

Presented by: Zhiyi Xue20

1European Institute of Oncology, Milan, Italy; 2Russian Academy of Medical Sciences, Moscow, Russia; 3Petrov Research Institute of

Oncology, St Petersburg, Russia; 4Clinical Oncology Dispensary, St Petersburg, Russia; 5Otto Wagner Hospital, Vienna, Austria; 6San

Camillo-Forlanini Hospital, Rome, Italy; 7Santa Maria della Misericordia Hospital, Perugia, Italy; 8Tel Aviv University, Tel Aviv, Israel; 9St

John of God Murdoch Hospital, Murdoch, WA, Australia; 10National Korányi Institute for Pulmonology, Budapest, Hungary; 11Azienda

Sanitaria-Universitaria Integrata, Udine, Italy; 12Ministry of Health of the Republic of Tatarstan, Kazan, Russia; 13Ordensklinikum

Elisabethinen, Linz, Austria; 14Department of Oncology, University of Turin, AOU San Luigi, Orbassano, Italy; 15Medical University of

Gdansk, Gdansk, Poland; 16Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA; 17Boehringer Ingelheim Italia S.p.A.,

Milan, Italy; 18Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 19Oncology Centre and Institute, Warsaw, Poland; 20Boehringer Ingelheim (China) Investment Co.,Ltd.

• We thank all patients and their families, and investigators and staff at all clinical sites, for their valuable participation in this study

• This study was funded by Boehringer Ingelheim

• Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Hannah Simmons, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this slide deck

Acknowledgements and Disclosures

Background

EGFRm+, EGFR mutation-positive; HR, hazard ratio; PFS, progression-free survival; RCT, randomized controlled trial

1. Sequist LV, et al. J Clin Oncol 2013;31:3327–34; 2. Wu Y-L, et al. Lancet Oncol 2014;15:213–22; 3. U.S. Food and Drug Administration. GILOTRIF® (afatinib). Highlights of Prescribing Information.

Accessed 9 August 2019; 4. European Medicines Agency. GIOTRIF® (afatinib). Summary of Product Characteristics. Accessed 9 August 2019; 5. Wu Y-L, et al. Ann Oncol 2019;30:171–210

RCTs are conducted in highly controlled settings, with strict inclusion criteria; therefore, it is important to support findings of afatinib efficacy and tolerability with real-world studies of broader

patient populations

These findings led to the approval of afatinib in China and several other countries for the first-line

treatment of patients with EGFRm+ NSCLC3–5

LUX-Lung 3 (Global) and 6 (China/South Korea/Thailand)

Median PFS with afatinib vs chemotherapy in patients with EGFRm+ NSCLC harboring common/uncommon mutations:

• LUX-Lung 3: 11.1 vs 6.9 months, HR=0.58; p=0.0011

• LUX Lung 6: 11.0 vs 5.6 months, HR=0.28; p<0.00012

• Afatinib demonstrated significantly improved efficacy outcomes and a manageable safety profile in patients with EGFRm+ NSCLC when compared with platinum-doublet chemotherapy in Phase III clinical trials1,2

• Patients with locally advanced/metastatic EGFRm+ NSCLC

• EGFR TKI-naïve

• ECOG PS 02

• Patients with asymptomatic brain metastases permitted*

Interim Analysis of a Prospective, Open-label, Multicenter, Phase IIIb Trial (NCT01853826)

*Previously treated, with SD for ≥4 weeks on stable doses of medication; †All patients who received at least one dose of afatinib (treated set) were included in the safety and efficacy analyses; ‡AEs were recorded at baseline and then every 28 days during treatment. Physical examinations and disease assessments were performed at the same time points; AE, adverse event; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, objective response rate; SD, stable disease; TKI, tyrosine kinase inhibitor; TTSP, time to symptomatic progression

Afatinib 40 mg/day until disease progression or other withdrawal criteria were met

Primary endpoint:† Safety (AEs in descriptive fashion)‡

Further endpoints: PFS, TTSP, ORR, DCR

Dose reduction to 30 or 20 mg/day was permitted based on individual tolerability

• 479 patients were enrolled and treated, including patients who are sometimes not eligible for RCTs1–3

Patient Disposition and Baseline Characteristics

*Missing (n=1); †Del19 or L858R mutations only (i.e., no uncommon mutations); ‡Uncommon EGFRmutations with/without common mutations; §Patients can appear in more than one mutation category; ¶ Percentage in relation to the number of patients in the uncommon cohort; Data cut-off: 30 April 2018

1. Sequist LV, et al. J Clin Oncol 2013;31:3327–34;2. Wu Y-L, et al. Lancet Oncol 2014;15:213–22;

3. Park K, et al. Lancet Oncol 2016;17:577–89

Uncommonmutation§

n (%)¶

ex20ins 37 (44)

G719S/A/C 12 (14)

T790M 12 (14)

L861Q 10 (12)

S768I 9 (11)

Other 18 (21)

2nd

81 (17%)

1st

374 (78%)

Line of therapy

≥3rd

24 (5%)

0171 (36%)

1271 (57%)

ECOG PS*

236 (8%)

Other14 (3%)

Caucasian465 (97%)

Race

Male165 (34%)

Female314 (66%)

Gender

No395 (83%)

Yes83 (17%)

Baseline brain metastases*

Uncommon‡

84 (18%)

EGFR mutation type*

Del19†

232 (48%)

L858R†

162 (34%)

PFS and TTSP

*Missing n=1; †Del19 or L858R mutations only (i.e., no uncommon mutations); ‡Uncommon EGFR mutations with/without common mutations; CI, confidence interval

0

0.0

6 12 18

Estim

ate

d p

robabili

ty

0.2

0.4

0.6

0.8

1.0

24 30 36 42 48 54

Time (months)Number at risk

479 332 237 167 113 72 55 41 21 2TTSP

n

PFS TTSP

Median, months (95% CI)

13.4 (11.8–14.5)

14.9 (13.8–17.6)

10.1

13.9

6.0

13.1

15.9

6.2

12.9

15.4

6.6

13.2

13.8

13.4

13.7

15.8

7.4

14.5

19.3

8.9

14.7

17.2

8.1

14.7

15.6

14.9

0 5 10 15 20

Time from start of afatinib (months)

479Overall population

395No

83Yes

3741st

812nd

24≥3rd

1710

362

232Del19†

162

Uncommon‡

Brain metastases*

Line of therapy

ECOG PS*

EGFR mutation type*

Median PFS

84

L858R†

1 271

Median TTSP

479 332 229 151 98 67 51 36 16 1PFS

AEs were Predictable and Manageable

*DR SAEs, n=39 (8%), most commonly diarrhea, n=15 (3%), dehydration, n=6 (1%), vomiting, n=5 (1%), all others n<4 (1%) each; †Percentage of overall population (N=479); ‡A total of 37 (8%) patients had DRAEs leading to treatment discontinuationDRAE, drug-related adverse event; DR SAE, drug-related serious adverse event

25

11

31

0

5

10

15

20

25

30

Diarrhea Rash

Pa

tien

ts (

%)

All grades,n (%)

Grade ≥3, n (%)

Any DRAE 462 (96)* 210 (44)

DRAEs in ≥10% of patients

Diarrhea 416 (87) 77 (16)

Rash 246 (51) 51 (11)

Paronychia 142 (30) 17 (4)

Mucosal inflammation 87 (18) 12 (3)

Dry skin 79 (16) 1 (<1)

Stomatitis 67 (14) 8 (2)

Skin fissures 51 (11) 3 (<1)

Nausea 50 (10) 5 (1)

Conjunctivitis 50 (10) 3 (<1)

Dermatitis acneiform 49 (10) 8 (2)

n=258 (54%)†40

mg/day20

mg/dayn=87 (18%)†

30 mg/day

Most common AEs leading to dose reduction

Most common DRAEs leading to treatment discontinuation‡

All other DRAEs leading to treatment discontinuation:

<1% each

Diarrhea and rash were the most common AEs leading to dose reduction, but led to few

treatment discontinuations

• Interim efficacy and safety results of this prospective study of afatinib in a near ‘real-world’ patient population with EGFRm+ NSCLC were consistent with findings from the pivotal LUX-Lung trials1–3

• Efficacy findings were encouraging, with an overall median PFS and TTSP of 13.4 and 14.9 months, respectively

– Prolonged efficacy was seen in patients with Del19 EGFRm+ disease (median PFS 15.9 months; TTSP 19.3 months)

• Activity of afatinib was also confirmed in patients who are sometimes excluded from RCTs

– Asymptomatic brain metastases (median PFS 10.1 months; TTSP 13.7 months)

– ECOG PS 2 (median PFS 6.2 months; TTSP 8.9 months)

– One/two prior lines of therapy (median PFS 13.2/6.6 months; TTSP 14.7/8.1 months)

• Diarrhea (87%) and rash (51%) were the most common DRAEs. Both were generally manageable with dose reduction, and led to few treatment discontinuations (3% and 1%, respectively)

Conclusions

1. Sequist LV, et al. J Clin Oncol 2013;31:3327–34 2. Wu Y-L, et al. Lancet Oncol 2014;15:213–22 3. Park K, et al. Lancet Oncol 2016;17:577–89

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ORR and DCR

ORR46% (n=218)

Best tumorresponse (N=479) n (%)

CR 25 (5)

PR 193 (40)

SD 193 (40)

PD 34 (7)

NE 23 (5)

CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response

DCR86% (n=411)

Any-cause AEs

All grades,n (%)

Grade ≥3, n (%)

Any AE 478 (>99) 315 (66)

Any SAE 202 (42) 171 (36)

Any-cause AEs in ≥10% of patients

Diarrhea 422 (88) 80 (17)

Rash 250 (52) 51 (11)

Paronychia 155 (32) 18 (4)

Asthenia 116 (24) 25 (5)

Mucosal inflammation 93 (19) 13 (3)

Dry skin 85 (18) 1 (<1)

Stomatitis 82 (17) 9 (2)

Dyspnea 76 (16) 14 (3)

Decreased appetite 73 (15) 8 (2)

Nausea 72 (15) 7 (1)

Fatigue 66 (14) 9 (2)

Vomiting 65 (14) 9 (2)

Conjunctivitis 68 (14) 4 (1)

Cough 69 (14) 0 (0)

Pyrexia 55 (11) 1 (<1)

Skin fissures 54 (11) 3 (1)

Pruritus 53 (11) 1 (<1)

Dermatitis acneiform 50 (10) 8 (2)